Although much research in drug delivery is currently directed at developing controlled time-released systems, the most common form of solid oral dosage delivery systems are those intended to be swallowed and dissolved rapidly in the mouth or gastrointestinal tract. It is often desirable to achieve fast release of active compounds of solid oral dosage forms. In order to facilitate the rapid release of active compounds disintegrants are often incorporated into the formulation of a tablet or capsule. Disintegrants are substances or mixtures of substances that are added to solid oral dosage forms such as tablets and capsules which facilitate the break-up or disintegration of the tablet or capsule contents into smaller particles which may dissolve more rapidly. Although the exact mechanism of disintegration is still unclear, water penetration is an indispensable step and nearly all disintegrants swell (Zhao N, Augsburger L L. The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of hydrochlorothiazide from directly compressed tablets. AAPS PharmSciTech. 2005 Sep. 20; 6(1):E120-6).
Nitric Oxide (NO) is a small reactive radical gas secreted by cells as a signaling molecule (Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 September; 6(12):3051-64). NO activity is largely controlled by regulating the factors responsible for synthesizing NO—Nitric Oxide Synthases (NOSs), such as the precursor molecules. All major nitric oxide synthase (NOS) isoforms and splice variants, including a muscle-specific splice variant, are expressed in the skeletal muscles of all mammals (Stamler J S, Meissner G. Physiology of nitric oxide in skeletal muscle. Physiol Rev. 2001 January; 81(1):209-237). Furthermore, the inner lining, or endothelium, of blood vessels uses NO to signal the surrounding smooth muscle to relax. This has the effect of dilating the artery increasing blood flow.
Muscle activation, i.e. contraction, has been correlated with NO signaling. NO production is increased in contracting muscle (Kobzik L, Reid M B, Bredt D S, Stamler J S. Nitric oxide in skeletal muscle. Nature. 1994 Dec. 8; 372(6506):546-8) and conversely, reducing muscle activity lowers NO levels (Tidball J G, Layergne E, Lau K S, Spencer M J, Stull J T, Wehling M. Mechanical loading regulates NOS expression and activity in developing and adult skeletal muscle. Am J Physiol. 1998 July; 275(1 Pt 1):C260-6). Furthermore, NO has been shown to be involved in glucose uptake in muscles undergoing exercise (Bradley S J, Kingwell B A, McConell G K. Nitric oxide synthase inhibition reduces leg glucose uptake but not blood flow during dynamic exercise in humans. Diabetes. 1999 September; 48(9):1815-21). Additionally, NO activity is increased by insulin and insulin-like growth factors which also stimulate the uptake of glucose (Kaliman P, Canicio J, Testar X, Palacin M, Zorzano A. Insulin-like growth factor-II, phosphatidylinositol 3-kinase, nuclear factor-kappaB and inducible nitric-oxide synthase define a common myogenic signaling pathway. J Biol Chem. 1999 Jun. 18; 274(25):17437-44)
Exogenous NO in humans has been shown to result in increases in measured strength (Folland J P, Maas H, Jones D A. The influence of nitric oxide on in vivo human skeletal muscle properties. Acta Physiol Scand. 2000 June; 169(2):141-8).
Thus, in muscles, NO is a signaling molecule which increases blood flow, increases glucose uptake and increases strength. Therefore, in terms of athletic performance it would be advantageous to increase and sustain levels of NO. Furthermore, it would be advantageous to expedite the increase of NO levels and activity through rapid delivery of NO-modulating compositions.